eicosanoids - power point presentaion

04/11/2023 Biochemistry for Medics 1

Biochemistry for Medicswww.namrata.co

Eicosanoids- Chemistry and Functions- A Brief Review


Prostaglandins and related compounds are collectively known

as Eicosanoids. Most are produced from Arachidonic acid, a 20-

carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic

acid).

Eicosanoids


Eicosanoids are classified in to two main groups-

1) Prostanoids

2) Leukotrienes and Lipoxins

Prostanoids are further sub classified in to three

groups-

a) Prostaglandins(PGs)

b) Prostacyclins(PGIs)

c) Thromboxanes (TXs)

Eicosanoids- Classification


All Prostanoids are considered to be derivatives of a cyclic

saturated fatty acid called Prostanoic acid.

Prostaglandins(PGs)

PGs can be divided into four major groups.- PG-E, PG-F,

PG-A and PG-B groups. PG-C and PG-D groups have also

been recognized.

PG- G and PG-H, considered as Primary PGs, are

intermediates in the synthesis of other prostaglandins.

Prostanoids


1) A trans double bond is present between 13th and 14th carbon atom2) An alpha oriented -OH group is present at 15th position 3) Differences in the 4main groups are due to difference in structure of cyclopentane ring.

Characteristic features of Structure of prostaglandins


There are 3 series of prostaglandins-

Series-1 contain one double bond at 13-14 position (Trans)Series-2 have two double bonds at 13-14 (trans) and 5-6 (Cis)Series-3 – have three double bonds at 13-14 (trans) , 5-6 (Cis) and 17-18 (Cis) positions.

Series of prostaglandins


1) Act as local hormones. 2)Show the effects near the site of synthesis(autocrine and Paracrine effects)3) Are not stored in the body4) Have a very short life span and are destroyed within seconds or few minutes5) Production increases or decreases in response to diverse stimuli or drugs6) Are very potent in action. Even in minute (nanogram concentration), biological effects are observed.

Characteristic features of prostaglandins


They have various roles in inflammation, fever, regulation of blood pressure, blood clotting, immune system modulation, control of reproductive processes, tissue growth, and regulation of the sleep/wake cycle.

Functions of Prostaglandins


1)Prostacyclins(PGI) contain another ring between 6 th and 9th carbon atoms

2) Thromboxanes (TX) have a six membered Oxane ring. There are three series for thromboxanes as well as for Prostacyclins.

Prostacyclins and Thromboxanes- Chemistry and Functions


They are synthesized in heart and vascular endothelial cells.-Inhibit platelet and leukocyte aggregation-Decrease T-cell proliferation ,lymphocyte migration and secretion of IL-1α and IL-2 -Induce vasodilatation and production of cAMP-prevent clot formation.

Functions of Prostcyclins


-They are synthesized by platelets. -Induce platelet aggregation, -promote vasoconstriction, lymphocyte proliferation -Bronchoconstriction and-Promote clot formation

Functions of Thromboxanes


Series -1 Eicosanoids are synthesized from dihomo-γ-linolenic acid (DGLA)

Series-2 from Arachidonic acid and

Series-3 are synthesized from Eicosa pentaenoic acid.

The major source of Arachidonic acid is through its release from cellular

stores.

Within the cell, it resides predominantly at the C–2 position of membrane

phospholipids and is released from there upon the activation of PLA2

Synthesis of Prostaglandins


Pathway is also called Cyclo-oxygenase pathway or cyclic pathway-The prostanoid signaling cascade begins with an external stimulus, most often the binding of a ligand to a cell surface receptor that activates phospholipase A2. This enzyme releases Arachidonic acid from its esterified form in membrane phospholipids such as phosphatidylethanolamine and phosphatidyl Inositol.

Steps of synthesis of Prostaglandins


-Arachidonate is converted to PGH2 by one of the isoforms of PGH synthase (PGHS-1 or -2), enzymes localized to the endoplasmic reticulum membrane and the nuclear envelope.- PGH2 is in turn metabolized to the prostanoid lipid signals (PGD2, PGE2, PGF2α, PGH2, PGI2, or TXA2) by one of the secondary enzymes that are named for the individual prostanoid produced. The type of prostanoid produced is determined by which downstream enzyme is present; usually one downstream enzyme predominates in a given cell.

Steps of synthesis of Prostanoids


Steps of synthesis of Prostanoids


Each PGHS isoform catalyzes two separate reactions. 1) The first reaction (Arachidonate to PGG2) involves insertion of two molecules of oxygen and Cyclization of the fatty acid backbone. This step is catalyzed by the cyclo-oxygenase activity of PGHS-1 or -2; it is these cyclo-oxygenase activities (also called COX-1 and COX-2) that are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).

2) The second step (PGG2 to PGH2) involves the reduction of the hydro peroxide on C15 to an alcohol and is catalyzed by the peroxidase activity of PGHS-1 or -2.

PGH synthase Isoforms


-There are two isoforms- PGH Synthase 1 and 2- PGH Synthase 1 – Basal form(constitutive)Many cells, including platelets and gastric mucosal cells, have moderate levels of the “basal” isoform, PGHS-1. Functions attributed to PGHS-1 include regulating hemostasis and vascular tone, renal function, and maintaining gastric mucosal integrity. PGH Synthase 2- Inducible form- present in a smaller number of cells, such as macrophages, vascular endothelial cells, and fibroblasts.

- have been implicated in cell proliferation, inflammation, carcinogenesis, and parturition.- PGHS-2 are induced in response to cytokines or mitogens.

Significance of PGH synthase isoforms


-Corticosteroids are anti-inflammatory because they prevent Phospholipase A2 expression, reducing arachidonate release.

-Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and derivatives of ibuprofen, inhibit cyclooxygenase activity of PGH

Synthase. They inhibit formation of prostaglandins involved in fever, pain, & inflammation.They inhibit blood clotting by blocking thromboxane formation in platelets.-Most NSAIDs inhibit both COX I & COX II. - Selective COX-2 inhibitors have been developed, (such as Celecoxib and Rofecoxib.- This selectivity has made the coxibs very useful for anti-inflammatory and antiproliferative therapy with reduced gastrointestinal side effects, but it also makes them ineffective as antiplatelet agents and consequently can increase cardiovascular risks.

Inhibitors of Prostanoid synthesis


Selective V/S Non Selective COX inhibition


1) All Arachidonic acid derivatives are quickly, in less than a few

minutes, inactivated in the body by several complex reactions.

"Switching off" of prostaglandin activity is partly achieved by a

remarkable property of cyclooxygenase—that of self-catalyzed

destruction; ie, it is a "suicide enzyme."

2)Furthermore, the inactivation of prostaglandins by 15-

hydroxyprostaglandin dehydrogenase is rapid.(OH group preset at

15th position is changed to a keto group)

Catabolism of Prostaglandins


The Leukotrienes are identified as LTs. -They are a family of conjugated trienes formed from eicosanoic acids in leukocytes, mastocytoma cells, platelets, and macrophages by the lipoxygenase pathway in response to both immunologic and nonimmunologic stimuli.

-Three different dioxygenases (dioxygenases) insert oxygen into the 5, 12, and 15 positions of Arachidonic acid, giving rise to hydroperoxides (HPETE).

- Only 5-lipoxygenase forms Leukotrienes.

Leukotrienes


Lipoxins are a family of conjugated tetraenes also arising in leukocytes.

They are formed by the combined action of more than one lipoxygenase.

Lipoxins


Steps of synthesis of Leukotrienes 5-Lipoxygenase, found in leukocytes, catalyzes conversion of arachidonate to 5-HPETE (5-hydroperoxy-eicosatetraenoic acid).

5-HPETE is converted to leukotriene-A4, which in turn may be converted to various other leukotrienes.

LTA4 is unstable and is converted to LTB4 in neutrophils and monocytes harboring LTA4 hydrolase. In mast cells and eosinophils, which harbor LTC4 synthase, LTA4 is converted to LTC4. The leukotrienes LTC4, LTD4, LTE4 and LTF4 are known as the peptidoleukotrienes or the cysteinyl leukotrienes because of the presence of amino acids.


Steps of synthesis of Leukotrienes


-Leukotrienes have roles in inflammation. -They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis.-Leukotrienes are also implicated in asthmatic constriction of the bronchioles. -The peptidoleukotrienes, LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis (SRSA).The subscript 4 in each molecule refers to the number of carbon-carbon double bonds present.

Functions of Leukotrienes


Three pathways exist for the synthesis of the lipoxins.

1) The "classic" pathway involves 5-LOX activity in leukocytes followed by 12-LOX action in platelets. 2)The action of 15-LOX in epithelial cell (such as in the airway) followed by 5-LOX action in leukocytes is the second major lipoxin synthesis pathway. 3)The action of aspirin on COX-2 in epithelial, or endothelial cells as wells as in monocytes results in the eventual production of the 15 epi-lipoxins (also referred to as aspirin triggered lipoxins, ATLs

Steps of synthesis of Lipoxins


Steps of Synthesis of Lipoxins


Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4, D4, and E4. This mixture of leukotrienes is a potent constrictor of the bronchial airway musculature. These leukotrienes together with leukotriene B4 also cause vascular permeability and attraction and activation of leukocytes and are important regulators in many diseases involving inflammatory or immediate hypersensitivity reactions, such as asthma.

Slow-reacting substance of anaphylaxis (SRS-A)


Aspirin inhibits the COX pathway and consequently diverts arachidonic acid metabolites to the LO pathway.

This also leads to a decrease in the levels of PGE2, the anti-inflammatory PG.

LTC4 synthase overexpression further increases the number of cysteinyl LTs, tilting the balance toward inflammation and broncho constriction

Reason for Aspirin induced Asthma


Reason for Aspirin induced Asthma


1)Cardiovascular uses- pulmonary arterial hypertension, peripheral vascular disease. for keeping the ductus arteriosus open until surgery in neonates carrying certain cardiac malformations and platelet anti-aggregating agents.2) Digestive Uses- indicated in the treatment of gastro duodenal ulcer and for the prevention of NSAID-induced ulcers. 3) Gynecological and obstetrical uses - They induce cervical dilatation and uterine contractions, particularly in late pregnancy. Used for medical termination of pregnancy and induction of labour.

Pharmacological applications of Eicosanoids


4) Ophthalmologic Use- lower intraocular pressure.

5) Anti- inflammatory use-Inhibitors of cyclo-oxygenases have anti-inflammatory properties and include nonsteroidal anti-inflammatory drugs or NSAID. The useful effects in therapeutics are-anti-inflammatory effectanalgesic effectantipyretic effectinhibition of platelet aggregation and decrease of thromboembolic risk (well-known with aspirin at low doses)

Pharmacological applications of Eicosanoids(Contd.)


6) Ulcerative Colitis- Mesalamine also called mesalazine or 5 aminosalicyclic acid has antiinflammatory properties in the colon and is used in the treatment of ulcerative colitis (Crohn's disease). Its mechanism of action is complex and as yet incompletely known: in addition to cyclo-oxygenases, it also inhibits lipoxygenases.7)Bronchial Asthma- PGE2 agonists and leukotrienes receptor antagonists are used for the treatment of bronchial asthma.

Pharmacological applications of Eicosanoids(Contd.)

eicosanoids - power point presentaion

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